Cannabis is the most widely abused illicit drug today. Cannabis use can substantially impair cognitive processes, including working memory, which in primates is dependent upon the circuitry of the dorsolateral prefrontal cortex (DLPFC). Cannabis use has also been associated with an increased risk of schizophrenia, a disorder characterized by impairments in working memory and dysfunction of the DLPFC. Interestingly, cannabis use during adolescence appears to especially increase the risk of both of these adverse consequences. Thus, adolescence represents a developmental time window of particular sensitivity to the effects of cannabis. The effects of cannabis are primarily mediated by the cannabinoid receptor 1 (CB1R). In primates, the DLPFC is densely innervated by CB1R-immunoreactive (CB1R-IR) axons that arise from the cholecystokinin (CCK)-containing class of GABA basket neurons and that synapse on the soma of pyramidal neurons. Thus, CB1R-positive axon terminals converge with inputs from parvalbumin (PV)-containing GABA neurons onto the perisomatic region of pyramidal cells, and these two sources of perisomatic inputs play complementary roles in the synchronization of pyramidal cell activity required for working memory. Because stimulation of the CB1R strongly suppresses the GABA inputs to pyramidal neurons from CCK-positive basket neurons, we hypothesize that cannabis use during adolescence alters the balance between the CCK/CB1R and PV inhibitory inputs to DLPFC pyramidal neurons. The resulting disturbance in the developmental trajectories of these perisomatic GABA inputs produces persistent circuitry alterations that impair the maturation of working memory performance. To test this hypothesis we will determine the postnatal developmental changes in the expression of CB1R mRNA and protein (Aim 1), the innervation patterns of CB1R-IR axons (Aim 2), and the electrophysiological consequences of CB1R activation (Aim 3) in the macaque monkey DLFPC, a model system that uniquely recapitulates the circuitry and protracted development of the human DLPFC. We will also assess the impact of chronic cannabis exposure during adolescence on working memory performance in monkeys (Aim 4) and on the maturation of perisomatic inputs to DLPFC pyramidal neurons (Aim 5). Thus, these studies will provide an explicit test of the biological events and mechanisms that make the adolescent brain especially vulnerable to the effects of cannabis. PUBLIC HEALTH RELEVANCE: Cannabis is the most widely abused illicit drug today. Use of cannabis during adolescence is associated with an increased risk of cognitive impairments and the later development of schizophrenia. These studies will provide an explicit test of the biological events and mechanisms that make the adolescent brain especially vulnerable to the effects of cannabis. [unreadable] [unreadable] [unreadable] [unreadable]